Abstract

Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic
β-cells. As a proinflammatory cytokine produced by β-cells or macrophages, interleukin (IL)-1β represents a potential therapeutic
target in diabetes. We reasoned IL-1β blockade could be combined with islet antigen-specific approaches involving glutamic
acid decarboxylase of 65kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CT) with anti-CD3.
Thus, we investigated whether anti-IL-1β antibody alone or combined with GAD65 vaccine could reverse diabetes development
in a virus-induced mouse model. Given alone, anti-IL-1β had no effect on diabetes while GAD65 plasmid resulted in 33% disease
reversal after 5-week observation. However, CT cured 53% of animals and prevented worsening of glycemic control in non-protected
individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased Foxp3+ regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b+/high cells was less frequent upon CT and its extent correlated with treatment success or failure. Altogether, our CT provided
prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1β monotherapy,
these data hold promise for treatment of type 1 diabetic patients with IL-1β blockade combined with antigen-specific vaccines.